Affiliation: Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.

ABSTRACT

Background: Mitochondria provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) in transcriptomic, proteomic, and metabolomic studies. Several mutations in mitochondrial DNA (mtDNA) sequence have been reported in SZ and BD patients.

Methodology/principal findings: Dorsolateral prefrontal cortex (DLPFC) from a cohort of 77 SZ, BD, and MDD subjects and age-matched controls (C) was studied for mtDNA sequence variations and heteroplasmy levels using Affymetrix mtDNA resequencing arrays. Heteroplasmy levels by microarray were compared to levels obtained with SNaPshot and allele specific real-time PCR. This study examined the association between brain pH and mtDNA alleles. The microarray resequencing of mtDNA was 100% concordant with conventional sequencing results for 103 mtDNA variants. The rate of synonymous base pair substitutions in the coding regions of the mtDNA genome was 22% higher (p = 0.0017) in DLPFC of individuals with SZ compared to controls. The association of brain pH and super haplogroup (U, K, UK) was significant (p = 0.004) and independent of postmortem interval time.

Conclusions: Focusing on haplogroup and individual susceptibility factors in psychiatric disorders by considering mtDNA variants may lead to innovative treatments to improve mitochondrial health and brain function.

pone-0004913-g004: The super haplogroup (U, K, UK) showed a shift in postmortem brain pH, and this finding was significant following permutation analysis.The histogram shows the frequency of the pH (bars) for the super haplogroup (red) compared to all other matrilineages (blue). The accumulated percentage (right y-axis) is shown as two lines with the super haplogroup (red line) and all other matrilineages (blue line). There were no subjects with a prolonged death, or agonal factors as rated according to the Hardy et al. scale [98]. PMI differences did not account for this significant effect, as PMI was equivalent between the super haplogroup and other haplogroups.

Mentions:
The present study design intentionally avoided some peri-mortem artifacts by pre-selecting subjects with rapid deaths and without recorded agonal factors in the autopsy database. The pH association did not appear spurious due to differences in assignment of cases and controls as the distribution was equally distributed for psychiatric cases and controls between U, K, UK super haplogroup and the remaining haplogroups. The pH shift towards the right for the U, K, UK super haplogroup and all other subjects (Fig. 4) showed that the lowest nine brain pH readings were all from subjects in the other super haplogroups besides U, K, or UK. Removing the lowest five pH subjects did not change the association of pH nor reduce the bootstrap significance of the difference between haplogroups. However, to exclude if the effect could be primarily related to factors like postmortem interval or agonal factors, we controlled for both effects. The PMI was not different between the U, K, UK super haplogroup and the remaining haplogroups, and including PMI in ANCOVA did not reduce the significance of the pH differences (p = 0.0007 with PMI as a covariate).

pone-0004913-g004: The super haplogroup (U, K, UK) showed a shift in postmortem brain pH, and this finding was significant following permutation analysis.The histogram shows the frequency of the pH (bars) for the super haplogroup (red) compared to all other matrilineages (blue). The accumulated percentage (right y-axis) is shown as two lines with the super haplogroup (red line) and all other matrilineages (blue line). There were no subjects with a prolonged death, or agonal factors as rated according to the Hardy et al. scale [98]. PMI differences did not account for this significant effect, as PMI was equivalent between the super haplogroup and other haplogroups.

Mentions:
The present study design intentionally avoided some peri-mortem artifacts by pre-selecting subjects with rapid deaths and without recorded agonal factors in the autopsy database. The pH association did not appear spurious due to differences in assignment of cases and controls as the distribution was equally distributed for psychiatric cases and controls between U, K, UK super haplogroup and the remaining haplogroups. The pH shift towards the right for the U, K, UK super haplogroup and all other subjects (Fig. 4) showed that the lowest nine brain pH readings were all from subjects in the other super haplogroups besides U, K, or UK. Removing the lowest five pH subjects did not change the association of pH nor reduce the bootstrap significance of the difference between haplogroups. However, to exclude if the effect could be primarily related to factors like postmortem interval or agonal factors, we controlled for both effects. The PMI was not different between the U, K, UK super haplogroup and the remaining haplogroups, and including PMI in ANCOVA did not reduce the significance of the pH differences (p = 0.0007 with PMI as a covariate).

Affiliation:
Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, United States of America.

ABSTRACT

Background: Mitochondria provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) in transcriptomic, proteomic, and metabolomic studies. Several mutations in mitochondrial DNA (mtDNA) sequence have been reported in SZ and BD patients.

Methodology/principal findings: Dorsolateral prefrontal cortex (DLPFC) from a cohort of 77 SZ, BD, and MDD subjects and age-matched controls (C) was studied for mtDNA sequence variations and heteroplasmy levels using Affymetrix mtDNA resequencing arrays. Heteroplasmy levels by microarray were compared to levels obtained with SNaPshot and allele specific real-time PCR. This study examined the association between brain pH and mtDNA alleles. The microarray resequencing of mtDNA was 100% concordant with conventional sequencing results for 103 mtDNA variants. The rate of synonymous base pair substitutions in the coding regions of the mtDNA genome was 22% higher (p = 0.0017) in DLPFC of individuals with SZ compared to controls. The association of brain pH and super haplogroup (U, K, UK) was significant (p = 0.004) and independent of postmortem interval time.

Conclusions: Focusing on haplogroup and individual susceptibility factors in psychiatric disorders by considering mtDNA variants may lead to innovative treatments to improve mitochondrial health and brain function.